Novel Diagnostics for Transthyretin Amyloid (Harvard University and Brigham & Women's Hospital)
This project, headed by Brian O’Nuallain, developed candidate antibodies for the noninvasive diagnosis and monitoring of amyloid disease caused by aggregates of wild-type transthyretin (TTR), a protein involved in the transport of thyroid hormone and vitamin A in the body. (See background information in the section for the complementary project in Dr. Sudhir Paul’s laboratory at the University of Texas-Houston Medical School.)
The current standard diagnostic test for TTR amyloid requires a cardiac biopsy, which is invasive and dangerous in the people most likely to be suffering from TTR aggregate disease, i.e. those who have sustained significant aging damage. Recent studies have stimulated more interest in using nuclear imaging techniques to label cardiac amyloid, but they too have their limitations. The main radiotracers being studied tend to pick up prior heart attack damage, calcification, and other forms of amyloid in addition to TTR aggregates. It is also not clear whether these radiotracers can pick up TTR amyloid at subclinical levels, the presence of which would make a person the ideal recipient of future rejuvenation therapies.
Improved diagnostics for TTR amyloid will allow clinicians to identify the best candidates for clinical trials for rejuvenation biotechnologies targeting TTR amyloid, and to monitor those therapies’ ability to clear TTR aggregates from aging tissues. This scenario would enable researchers to evaluate candidate therapies’ efficacy and safety in real time instead of relying on biopsies, autopsies, or waiting until the end of a trial to see if treatment improved survival. Also, because TTR amyloidosis is difficult to diagnose with existing methods, it is greatly under-diagnosed and often confused with congestive heart failure from other causes.
The development of a convenient, noninvasive means of identifying harmful levels of accumulated TTR is thus a high priority for the Foundation. Such a test would ensure that people who could benefit from TTR-targeting therapies could get rapid and safe access to such therapies once they become available, saving the most lives and improving cardiac function as early as possible.
Using strategies previously employed to develop diagnostic antibodies against other forms of amyloid disease, the Harvard TTR aggregate diagnostic team generated more than 20 distinct monoclonal antibodies specific to TTR aggregates. Five proved themselves to be especially promising as candidate diagnostics, as they are highly selective for TTR aggregates, and retain their useful properties in human blood as well as in isolated systems. Furthermore, one candidate diagnostic antibody could have some therapeutic potential as well. The Harvard group has shown for the first time that soluble TTR aggregates derived directly from an actual patient heart are toxic to heart cells — and, importantly, that their lead antibody partially protects heart cells against this toxicity.